Adjuvant Therapy for Endometrial Cancer

(RAINBO Trial)

Recruiting at 13 trial locations

Overseen By Carien L Creutzberg, MD PhD

Age: 18+

Sex: Female

Trial Phase: Phase 2 & 3

Sponsor: Leiden University Medical Center

Must not be taking: PARP inhibitors, PD(L)1 inhibitors, CYP3A inhibitors, CYP3A inducers

Disqualifiers: Other malignancy, Prior pelvic radiation, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 1-2 years

1615 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests new treatments for endometrial cancer based on the cancer's genetic makeup. Patients are grouped by their cancer type and given tailored treatments combining radiation, chemotherapy, and targeted drugs. The aim is to find the most effective and least harmful treatments for each specific type of endometrial cancer. Dostarlimab has shown promising results in treating endometrial cancer, with a trial curing 100% of CRC patients without severe adverse events.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) for specific drugs. If you are taking strong or moderate CYP3A inhibitors or inducers, you will need to stop them 2 to 5 weeks before starting the trial medication. Please consult with the trial team for guidance on your specific medications.

What data supports the effectiveness of the drug combination including medroxyprogesterone acetate for endometrial cancer?

Research shows that medroxyprogesterone acetate, a component of the treatment, has been effective in treating advanced endometrial cancer, with some patients experiencing partial responses and prolonged survival. Additionally, combination therapies including medroxyprogesterone acetate have shown promising results in achieving complete remission in some cases of recurrent endometrial cancer. ^{1 2 3 4 5}

Is the treatment generally safe for humans?

Medroxyprogesterone acetate (Depo-Provera) has been shown to be safe in various studies, with minor side effects like menstrual irregularities and amenorrhea (absence of menstruation) reported. It is effective and safe for conditions like endometrial hyperplasia and has been used in contraceptive formulations with a good safety profile. ^{1 6 7 8 9}

How does the drug used in adjuvant therapy for endometrial cancer differ from other treatments?

The adjuvant therapy for endometrial cancer may involve the use of medroxyprogesterone acetate (MPA), which is a hormone therapy that can be taken orally and is used to treat hormone-dependent tumors. This treatment is unique because it offers an alternative to conventional treatments, especially for maintenance therapy, and is easy to administer over long periods. ^{1 2 4 10 11}

Research Team

Melanie E Powell, Md PhD

Principal Investigator

Barts Health NHS Trust, London, United Kingdom (NSMP-ORANGE trial)

Jessica N McAlpine, Md PhD

Principal Investigator

University of British Columbia,Vancouver, Canada (POLEmut-BLUE trial)

Alexandra Leary, Md PhD

Principal Investigator

Institute Gustave Roussy, Villejuif, France (p53abn-RED trial)

Judith R Kroep, MD PhD

Principal Investigator

Leiden University Medical Center, Leiden, The Netherlands (MMRd-GREEN trial)

Emma J Crosbie, Md PhD

Principal Investigator

St Mary's Hospital, Manchester, United Kingdom (NSMP-ORANGE trial)

Kathy Han, Md PhD

Principal Investigator

Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada (POLEmut-BLUE trial)

Eligibility Criteria

This trial is for patients with endometrial cancer, categorized by their cancer's molecular profile. They must have a WHO performance status of 0-2, weigh over 30 kg, and have no distant metastases or major surgeries within the last 28 days. Patients should not have had prior treatments that conflict with the trial drugs and must be able to follow up for treatment.

Inclusion Criteria

I have had my uterus and both ovaries removed with no visible disease left.

I can take care of myself but may not be able to do heavy physical work.

Patients must be accessible for treatment and follow-up

Exclusion Criteria

I have had another type of cancer in the last 5 years.

I have had radiation therapy to my pelvic area before.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive adjuvant chemoradiation followed by specific therapies based on molecular profile: olaparib, durvalumab, progestogens, or no adjuvant therapy

1-2 years

Follow-up

Participants are monitored for recurrence-free survival and other outcomes

3-5 years

Treatment Details

Interventions

• Durvalumab
• Medroxyprogesterone Acetate
• Megestrol Acetate
• Olaparib

Trial Overview The RAINBO program includes four trials testing new adjuvant therapies in endometrial cancer based on molecular profiles: p53abn-RED for p53 abnormal cancers; MMRd-GREEN for mismatch repair deficient; NSMP-ORANGE when there's no specific profile; POLEmut-BLUE for POLE mutant cancers.

Participant Groups

Group I: p53abn-RED trial: experimental Experimental Treatment 4 Interventions

Adjuvant radiotherapy and chemotherapy followed by olaparib (lynparza), 300 mg twice daily, for one year

Group II: POLEmut-BLUE trial: main cohort Experimental Treatment 1 Intervention

No adjuvant therapy in women with: * stage IA (not confined to polyp), grade 3, pN0, with or without LVSI * stage IB, grade 1 or 2, pNx/N0, with or without LVSI * stage IB, grade 3, pN0, without substantial LVSI * stage II (microscopic), grade 1 or 2, pN0, without substantial LVSI

Group III: POLEmut-BLUE trial: exploratory cohort Experimental Treatment 3 Interventions

No adjuvant therapy or vaginal brachytherapy or pelvic external beam radiotherapy in women with: * stage IA grade 3 - stage III not included in main cohort of the POLEmut-BLUE trial * Multiple molecular classifiers Stage IA (not confined to polyp), grade 3 - Stage III

Group IV: NSMP-ORANGE trial: experimental Experimental Treatment 4 Interventions

Adjuvant radiotherapy followed by oral progestagens (medroxyprogesterone acetate or megestrol acetate) for two years

Group V: MMRd-GREEN trial: experimental Experimental Treatment 3 Interventions

Adjuvant radiotherapy combined with and followed by durvalumab, 1500 mg intravenous once every 4 weeks for in total 1 year (13 cycles)

Group VI: MMRd-GREEN trial: control Active Control 3 Interventions

Adjuvant pelvic external beam radiotherapy +/- chemotherapy

Group VII: NSMP-ORANGE trial: control Active Control 3 Interventions

Adjuvant radiotherapy and chemotherapy

Group VIII: p53abn-RED trial: control Active Control 3 Interventions

Adjuvant radiotherapy and chemotherapy

Who Is Running the Clinical Trial?

Leiden University Medical Center

Lead Sponsor

Trials

580

Recruited

623,000+

Dutch Gynaecological Oncology Group

Collaborator

Trials

3

Recruited

2,500+

University College London (sponsor NSMP-ORANGE trial)

Collaborator

Trials

1

Recruited

1,600+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

National Cancer Institute, France

Collaborator

Trials

172

Recruited

290,000+

Cancer Research UK & UCL Cancer Trials Centre

Collaborator

Trials

4

Recruited

3,700+

Leiden University Medical center (sponsor MMRd-GREEN trial)

Collaborator

Trials

1

Recruited

1,600+

Institute Gustave Roussy (sponsor p53abn-RED trial)

Collaborator

Trials

1

Recruited

1,600+

Comprehensive Cancer Centre The Netherlands

Collaborator

Trials

22

Recruited

18,400+

Findings from Research

In a pilot study of 50 women with advanced breast and endometrial cancer, high-dose oral medroxyprogesterone acetate (MPA) showed partial responses in 30% of patients for both types of cancer, indicating its potential effectiveness.

Despite a lower response rate compared to injectable forms, oral MPA offers a convenient long-term treatment option for hormone-dependent tumors, making it a viable alternative for maintenance therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Oral high doses of medroxyprogesterone acetate (MPA) in the treatment of advanced phases of breast and endometrial cancer]. Bernardo-Strada, MR., Imparato, E., Aspesi, G., et al.[2013]

Two patients with recurrent endometrial adenocarcinoma achieved complete remission after treatment with a combination of melphalan, 5-fluorouracil, and medroxyprogesterone acetate.

The remission was confirmed through a second-look operation, indicating the potential efficacy of this treatment regimen for this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination chemotherapy for advanced endometrial adenocarcinoma. Deppe, G., Bruckner, HW., Cohen, CJ.[2019]

ADCK3 has been identified as a crucial regulator in endometrial carcinoma (EC) cells' response to medroxyprogesterone acetate (MPA), where its loss reduces MPA-induced cell death, indicating a potential resistance mechanism.

Activating the p53-ADCK3 regulatory axis using the small-molecule compound Nutlin3A can enhance the effectiveness of MPA treatment, suggesting a new strategy to improve conservative treatment outcomes for EC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genome-wide CRISPR screening reveals ADCK3 as a key regulator in sensitizing endometrial carcinoma cells to MPA therapy. Zhang, Z., Zhang, M., Zhou, J., et al.[2023]

A 71-year-old woman with recurrent, metastatic endometrial cancer experienced significant clinical stability and a good quality of life for approximately 57 months while treated with a combination of tamoxifen and megestrol acetate, highlighting the potential effectiveness of this endocrine therapy.

This case suggests that combination endocrine therapy can be a viable treatment option for patients with recurrent, ER/PR-positive endometrial cancer, offering substantial long-term benefits with minimal side effects, even after multiple prior treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case report: prolonged durable clinical benefit and low toxicity from combination endocrine therapy in a patient with recurrent endometrial carcinoma. Cheng, JM., Gaillard, S., Beavis, AL., et al.[2023]

In a study of 22 patients with endometrial cancer, a combination treatment of Megestrol acetate, Beta interferon, and Tamoxifen led to significant increases in estrogen and progesterone receptor levels, indicating a potential mechanism for enhancing treatment efficacy.

Out of the 12 patients treated, 41.67% achieved complete remission and 33.34% achieved partial remission, suggesting that this treatment regimen may be effective for a substantial portion of patients, although there was a notable risk of serious adverse events, including one death from a stroke.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tamoxifen, megestrol acetate, and beta interferon in endometrial cancer. Cardone, A., Tolino, A., Di Serio, C., et al.[2020]

Depot medroxyprogesterone acetate (DMPA) and medroxyprogesterone acetate/estradiol cypionate (MPA/E(2)C) are highly effective and safe injectable contraceptive options for women, with DMPA notably reducing the risk of endometrial cancer by 80%.

Both contraceptive methods may cause minor side effects, such as menstrual irregularities and amenorrhea with DMPA, highlighting the importance of patient counseling for successful long-term use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current options for injectable contraception in the United States. Kaunitz, AM.[2013]

A single subcutaneous injection of 150 mg or 300 mg of Depo-Provera effectively suppressed ovulation for up to 7 months in 42 women, indicating its potential as a long-acting contraceptive method.

The pharmacokinetics of the 150 mg Depo-Provera injection showed similar peak and trough hormone levels compared to two injections of Depo-SubQ Provera 104, suggesting that it could be administered every 6 months with a grace period for reinjections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical trial to evaluate pharmacokinetics and pharmacodynamics of medroxyprogesterone acetate after subcutaneous administration of Depo-Provera. Halpern, V., Brache, V., Taylor, D., et al.[2021]

The investigational drug TV-46046, when administered subcutaneously, showed a higher incidence of injection site reactions (ISRs), particularly hypopigmentation, compared to the reference drug Depo-subQ Provera 104, with 44% of participants experiencing this reaction after receiving undiluted TV-46046.

Despite the higher rate of ISRs, the overall injection pain was minimal and quickly resolved, indicating that TV-46046 is a safe candidate for further clinical testing as a long-acting contraceptive, although the delayed onset of hypopigmentation requires further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized crossover study to evaluate local tolerability following subcutaneous administration of a new depot medroxyprogesterone acetate contraceptive formulation. Halpern, V., Wheeless, A., Brache, V., et al.[2023]

In a study of 146 women aged 35 to 50 with endometrial hyperplasia, Depo-Provera was found to be significantly more effective than norethisterone acetate in achieving regression of nonatypical endometrial hyperplasia, with 91.8% of women responding to Depo-Provera compared to 67.1% for NETA.

The study indicates that Depo-Provera is a safe and effective treatment option for endometrial hyperplasia without atypia, with moderate differences in adverse effects between the two treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Depo-Provera Versus Norethisterone Acetate in Management of Endometrial Hyperplasia Without Atypia. Nooh, AM., Abdeldayem, HM., Girbash, EF., et al.[2018]

In a study involving 218 patients with Stage I endometrial carcinoma, neoadjuvant treatment with medroxyprogesterone acetate (MPA) did not significantly improve overall survival compared to the control group that received no adjuvant treatment.

After a minimum follow-up of 5 years, the survival rates were similar between the treatment group (83.7% at 5 years) and the control group (78.9% at 5 years), indicating that MPA may not provide a survival benefit in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stage I endometrial carcinoma: the role of neoadjuvant progesterone therapy. Haylock, BJ., Murrell, DS., Bourne, H., et al.[2019]

In a randomized trial of 388 patients with early endometrial cancer, adjuvant hormonal therapies (medroxyprogesterone acetate and tamoxifen) did not significantly improve disease-free or overall survival rates compared to observation alone after surgical treatment.

While tamoxifen did not enhance survival outcomes, it was associated with some beneficial effects on coexisting health issues, and it had fewer severe side effects compared to medroxyprogesterone acetate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant endocrine treatment with medroxyprogesterone acetate or tamoxifen in stage I and II endometrial cancer--a multicentre, open, controlled, prospectively randomised trial. von Minckwitz, G., Loibl, S., Brunnert, K., et al.[2019]

References

1. Italy pubmed.ncbi.nlm.nih.gov

[Oral high doses of medroxyprogesterone acetate (MPA) in the treatment of advanced phases of breast and endometrial cancer]. [2013]

2. United States pubmed.ncbi.nlm.nih.gov

Combination chemotherapy for advanced endometrial adenocarcinoma. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Genome-wide CRISPR screening reveals ADCK3 as a key regulator in sensitizing endometrial carcinoma cells to MPA therapy. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Case report: prolonged durable clinical benefit and low toxicity from combination endocrine therapy in a patient with recurrent endometrial carcinoma. [2023]

5. Singapore pubmed.ncbi.nlm.nih.gov

Tamoxifen, megestrol acetate, and beta interferon in endometrial cancer. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Current options for injectable contraception in the United States. [2013]

7. United States pubmed.ncbi.nlm.nih.gov

Clinical trial to evaluate pharmacokinetics and pharmacodynamics of medroxyprogesterone acetate after subcutaneous administration of Depo-Provera. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

A randomized crossover study to evaluate local tolerability following subcutaneous administration of a new depot medroxyprogesterone acetate contraceptive formulation. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Depo-Provera Versus Norethisterone Acetate in Management of Endometrial Hyperplasia Without Atypia. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Stage I endometrial carcinoma: the role of neoadjuvant progesterone therapy. [2019]

11. England pubmed.ncbi.nlm.nih.gov

Adjuvant endocrine treatment with medroxyprogesterone acetate or tamoxifen in stage I and II endometrial cancer--a multicentre, open, controlled, prospectively randomised trial. [2019]